The table below highlights all of the cell lines that are included in the analyses and the types that they are annotated as:
The list of COSMIC genes was downloaded from https://cancer.sanger.ac.uk/cosmic/census on 1/11/2020 selecting ‘both tiers’.
Mutation plot counting the total number of mutations we cell line using only WES data (from either Sanger or the Broad).
Mutation plot counting the total number of mutations per cell line using only WGS data.
Starting from the DepMap mutations MAF file, filter for mutations that were called using WGS. Count the total number of mutations called in each sample and then plot the results. Sort sample by the median count by lineage.
MutSig2CV was run on samples separately for MAFs for Broad WES, Sanger WES, and COSMIC only mutations. This was done by downloading MutSig2CV from https://software.broadinstitute.org/cancer/cga/sites/default/files/data/tools/mutsig/MutSig2CV.tar.gz. Following the README, this was installed along with the MCR in a VM running linux (VirtualBox 6.1.6 with 12GB RAM, Ubuntu 18.04.03 LTS).
MutSig2CV removes cell lines that appear to be duplicates (having almost identical mutational patterns) and then infers a mutation rate. These mutation rates were used for the plot below.
MutSig2CV analyzes somatic point mutations discovered in DNA sequencing, identifying genes mutated more often than expected by chance given inferred background mutation processes. MutSig2CV consists of three independent statistical tests, described briefly below:
Abundance (CV): The most important step for inferring genes’ mutational significance is to properly classify whether the gene is highly mutated relative to some background mutation rate (BMR), which varies on a macroscopic level across patients and genes and on a microscopic level across sequence contexts. MutSig accounts for all three of these to renormalize BMR on a per-gene, -patient, and -context level.
Clustering (CL): Genes often harbor mutational hotspots, specific sites that are frequently mutated. While abundance calculations bin mutations on the gene level, clustering bins mutations on the local site level, which allows MutSig to differentiate between genes with uniformly distributed mutations and genes with localized hotspots, assigning higher significance to the latter.
Conservation (FN): MutSig uses evolutionary conservation as a proxy for determining the functional significance of a mutated site. It assumes that genetic sites highly conserved across vertebrates have greater functional significance than weakly conserved sites. MutSig assigns a higher significance to genes that experience frequent mutations in highly conserved sites.
In the plots below, we look only at the COSMIC genes and ignore any of the significance thresholds from MutSig2CV. The frequency of mutations in these genes is determined by counting the number of cell lines that had this mutation and normalizing to the total number of cell lines evaluated.
The table below outlines all of the genes that passed this criteria (hover over column names for meaning):
The plot below shows % of cell lines with a damaging, missense, or hotspot mutation in the given gene.
Look at the relationship of dependency and mutation rate with NNMD (separation of positive and negative controls) and CAS9 activity (measured as % GFP remaining after CRISPR-Cas9 directed GFP editting, i.e. lower number indicates higher CAS9 activity).
devtools::session_info()
## ─ Session info ───────────────────────────────────────────────────────────────
## setting value
## version R version 3.6.2 (2019-12-12)
## os macOS Catalina 10.15.6
## system x86_64, darwin15.6.0
## ui X11
## language (EN)
## collate en_US.UTF-8
## ctype en_US.UTF-8
## tz America/New_York
## date 2020-08-18
##
## ─ Packages ───────────────────────────────────────────────────────────────────
## package * version date lib source
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##
## [1] /Library/Frameworks/R.framework/Versions/3.6/Resources/library